Alveolar hypoxia, as occurs with ascent to high altitude or chronic lung diseases, results in hypoxic pulmonary vasoconstriction (HPV). Exaggerated HPV causes high altitude pulmonary edema (HAPE) (Bartsch P, et al., J Appl Physiol 98: 1101-1110 (2005)) and may complicate the course of patients with chronic cardiopulmonary disease. Despite extensive study, the exact cellular mechanisms by which hypoxia induces HPV remain poorly understood. HPV is generally believed to require Ca2+ influx into pulmonary arterial smooth muscle cells (PASMCs), as HPV is attenuated by removal of extracellular Ca2+ and by antagonists of voltage-gated Ca2+ channels (McMurtry I. F., et al., Circ Res 38: 99-104 (1976); Naeije R., et al., Chest 82: 404-410 (1982); Redding G. J., et al., Am Rev Respir Dis 129: 785-789 (1984); Simonneau G., et al., N Engl J Med 304: 1582-1585 (1981); Stanbrook H. S., et al., Am Rev Respir Dis 130: 81-85 (1984); Suggett A. J., et al., Clin Exp Pharmacol Physiol 7: 263-274 (1980); Tucker A., et al., Proc Soc Exp Biol Med 151: 611-614 (1976). HPV can also be modulated by changes in intracellular pH (pHi) (Raffestin B., et al., J Appl Physiol 63: 2524-2531 (1987) and extracellular pH (Loeppky J. A., et al., J Appl Physiol 72: 1787-1797 (1992)).
The oral carbonic anhydrase (CA) inhibitor acetazolamide (AZ) is frequently used for prevention and treatment of acute mountain sickness (AMS) and to augment ventilation for high altitude acclimatization (Swenson E. R., et al., Eur Respir J 12:1242-1247 (1998); Swenson E. R., Resp Physiol Neurobiol. 151(2-3): 209-16 (2006)). When taken prior to ascent, AZ can prevent the development of acute mountain sickness by its effects on renal bicarbonate reabsorption and chemoreceptor activity to increase ventilation and increase arterial oxygenation. As a respiratory stimulant AZ raises alveolar PO2 and might by this mechanism blunt HPV and prevent HAPE, as do other pulmonary vasodilators that reduce HPV, such as nifedipine (Bartsch P., et al., N Engl J Med 325: 1284-1289 (1991)). Work in intact animals and isolated perfused lung preparations, has demonstrated that AZ attenuates the magnitude of HPV and slows the onset of the response (Deem S., et al., Respir Physiol 123: 109-119 (2000); Emery C. J., et al., Bull Eur Physiopathol Respir 13: 763-776 (1977); Hohne C., et al., J Appl Physiol 97: 515-521 (2004)), although the cellular mechanism by which this occurs remains uncertain. Although in vivo AZ might blunt HPV additionally by its respiratory effect, a direct effect independent of ventilation-induced changes in alveolar PO2 is evident since AZ inhibits HPV when ventilation, alveolar PO2 and PCO2 are carefully controlled or held constant (Deem S., et al., Respir Physiol 123: 109-119 (2000); Emery C. J., et al., Bull Eur Physiopathol Respir 13; 763-776 (1977); Hohne C., et al., J Appl Physiol 97:515-521 (2004)). Although originally developed as a diuretic with primary action on the kidney, vascular smooth muscle contains CA (Berg J. T., et al., J Histochem Cytochem 52: 1101-1106 (2004)) and AZ has been proposed to have direct effects on smooth muscle function in systemic blood vessels independent of its diuretic actions. The mechanisms involved in the vasodilatory effect of AZ on systemic vascular smooth muscle (Pickkers P., et al., Br J Pharmacol 132: 443-450 (2001)), which may include modulation of K+ channels, membrane potential, Ca2+ signaling or intracellular pH (pHi), are just beginning to be explored. For example, in various cell types carbonic anhydrase inhibitors block Ca2+ channels (Gottfried J. A. and Chesler M., J Neurophysiol 74: 2774-2777 (1995); Jahromi S. S., et al., Brain Res 872: 20-28 (2000); McNaughton N. C., et al., J Pharmacol Sci 95: 240-247 (2004); Zhang X., et al., Epilepsia 41 Suppl 1: S52-60 (2000)), inhibit a Cl−-dependent ATPase (Chipperfield A. R., et al., Biochem Biophys Res Commun 194: 407-412 (1993)) and activate Ca2+-activated K+ channels (Pickkers P., et al., Br J Pharmacol 132: 443-450 (2001); Tricarico D., et al., Ann Neurol 48: 304-312 (2000); Tricarico D., et al., Faseb J 18: 760-761 (2004)). The effect of AZ and/or carbonic anhydrase inhibition on pulmonary artery smooth muscle cell (PASMC) function is unknown.
The present invention is directed toward overcoming these deficiencies in the art.